Dr Barry Laird Clinician Scientist in Palliative Medicine University of Edinburgh and the European Palliative Care Research Centre (PRC)

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1 1 Dr Barry Laird Clinician Scientist in Palliative Medicine University of Edinburgh and the European Palliative Care Research Centre (PRC) 2 Acknowledgements Prof Marie Fallon (group lead EPAS) University of Edinburgh Prof Ken Fearon NTNU Prof P Klepstad, Prof S Kaasa, Prof P Fayers University of Glasgow Prof D McMillan 1

2 3 Symptom Prevalence in Advanced Cancer Teunissen et al, JPSM Are cancer pain and depression interdependent? Laird BJA, Boyd AC, Colvin LA, Fallon MT. Psycho-oncology DOI: /pon.1431 Pain intensity, duration and certain descriptors (MPQ) associated with depression. Pain and depression both highly prevalent Certain pain features correlated with depression 2

3 5 6 Symptom Cluster In advanced cancer, a median of 11 symptoms (range 1 27) are present commonly (Walsh et al., 2000). Symptoms can simply co exist Symptoms can co exist and be related Symptoms can co exist and share a common pathophysiology Symptom cluster: three or more concurrent symptoms that are related to each other is the most appropriate definition (Dodd et al., 2001b). 3

4 7 Pain, depression and fatigue as a symptom cluster in advanced cancer. Laird et al. Journal of Pain and Symptom Management Vol 42, No1, 2011 n=654 Patients with moderate under nutrition EORTC QLQ C30 Cut offs based on thresholds Multivariate and regression analyses run 8 Trial A (n=473) Trial B (n=181) Depression* Fatigue** Pain*** Observed Expected Observed Expected Prevalence Prevalence@ Prevalance Prevalence@ No No No 130 (27.5%) 71.2 (15.1%) 58 (32.0%) 39.0 (21.6%) No No Yes 25 (5.3%) 48.7 (10.3%) 23 (12.7%) 29.6 (16.3%) No Yes No 40 (8.5%) 58.7 (12.4%) 11 (6.1%) 22.4 (12.4%) No Yes Yes 24 (5.1%) 40.2 (8.5%) 16 (8.8%) 17.0 (9.4%) Yes No No 62 (13.1%) 82.6 (17.5%) 23 (12.7%) 26.4 (14.6%) Yes No Yes 42 (8.9%) 56.5 (11.9%) 11 (6.1%) 20.0 (11.0%) Yes Yes No 49 (10.4%) 68.3 (14.4%) 11 (6.1%) 15.1 (8.4%) Yes Yes Yes 101 (21.4%) 46.6 (9.9%) 28 (15.5%) 11.5 (6.3%) 4

5 9 Pain, Depression, Fatigue Symptom Cluster Pain, depression and fatigue exists as a specific symptom cluster in advanced cancer patients. Between Two and four times the number of patients with all three symptoms than would be expected. (p<0.001) Each symptom can occur in isolation and every possible pair of symptoms can occur without the third being present. This further supports the existence of pain, depression and fatigue as a specific symptom cluster. First study to demonstrate this cluster 10 Cytokine Induced Sickness Behaviour Administration of inflammatory agents and pro inflammatory cytokines results in cytokine induced sickness behaviour (Konsman et al., 2002, Dantzer, 2004). Cytokine induced sickness behaviour produces pain and behavioural changes which are comparable with pain, depression and fatigue in humans (Yirmiya, 1996, Watkins and Maier, 2000). In humans the response to infection, results in increased production of pro inflammatory cytokines (IL 1, IL 6 and TNFalpha). These pro inflammatory cytokines correlate with clinical symptoms which mirror animal models of sickness behaviour (Vollmer Conna et al., 2004). Cytokine induced sickness behaviour resulting in pain, depression and fatigue, has been shown to exist not demonstrated in cancer... 5

6 11 Inflammation & Cancer Inflammation predisposes to certain tumour types Inflammation implicated in oncogenic mutations & experimental animal models of tumour development 1 Inflammation can be a result of cancer. Targeting inflammation can reduce cancer risk and cancer spread. 7 th hallmark of cancer 1.Mantovani Nature 2008;

7 13 Measuring inflammation CRP Reliable biomarker of SI in cancer Half life of CRP is 19hrs CRP is produced under the control of interleukin 6 (IL 6). IL 6 pro inflammatory cytokine and is a critical mediator of inflammation. IL 6 concentrations are highly correlated with CRP CRP serves as a biomarker for systemic inflammation ~ IL

8 15 Aim: assess relationship between pain and systemic inflammation cohort of cancer patients; Secondary analysis of BH 80 and Scotia trials (JCO, Gut) n=449, groups well matched CRP used (surrogate IL 6) 16 Relationship between pain and CRP Trial 1 N=275 CRP Trial 2 N=174 CRP Pain Pain Pain Pearson Correlation Significance (2-tailed) Number of patients

9 17 Pain and systemic inflammation Pain associated with IL 6 Supported in basic science work (IL 6 knockout mice) (Ramer 1998) IL 6 admin results in allodynia and hyperalgesia (DeLeo 1996) Inflammatory pain IL 6 increased Glial activation and IL 6 (Wieseler Frank 2004) 18 Cancer Symptoms Pain Depression Fatigue Opioids Symptom Clusters Systemic inflammation Prognosis 9

10 19 Modulating the inflammatory response to treat symptoms? 20 10

11 21 Symptoms linked Symptoms related to inflammation Inflammation related to prognosis Are symptoms related to prognosis? 22 World Health Organization definition of palliative care: an approach that improves the quality of life of patients and their families facing the problem associated with life threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychological and spiritual 11

12 23 Systemic Inflammatory Response ANABOLIC BLOCKADE Cachexia Anorexia Physical Inactivity Interventions should be multimodal tackling all of these issues simultaneously 24 premenac Study A multicentre, open, randomized phase II study comparing a multimodal intervention (oral nutritional supplements, celecoxib and physical exercise) for cachexia versus standard cancer care. (EudraCT number: ) Modulating the inflammatory response on a background of optimal symptom control. 12

13 25 Thank you. 13